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Preventing Atrial Fibrillation With Treatments for Diabetes Mellitus

2020; Lippincott Williams & Wilkins; Volume: 141; Issue: 15 Linguagem: Inglês

10.1161/circulationaha.120.045864

1524-4539

Christopher B. Granger, Kenneth W. Mahaffey,

Atrial Fibrillation Management and Outcomes

HomeCirculationVol. 141, No. 15Preventing Atrial Fibrillation With Treatments for Diabetes Mellitus Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPreventing Atrial Fibrillation With Treatments for Diabetes Mellitus Christopher B. Granger, MD and Kenneth W. Mahaffey, MD Christopher B. GrangerChristopher B. Granger Christopher B. Granger, MD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701. Email E-mail Address: [email protected] Duke Clinical Research Institute, Durham, NC (C.B.G.). and Kenneth W. MahaffeyKenneth W. Mahaffey The Stanford Center for Clinical Research, Department of Medicine, Stanford School of Medicine, Palo Alto, CA (K.W.M.). Originally published13 Apr 2020https://doi.org/10.1161/CIRCULATIONAHA.120.045864Circulation. 2020;141:1235–1237This article is a commentary on the followingEffect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes MellitusArticle, see p 1227In 2008, the US Food and Drug Administration issued guidance to the pharmaceutical industry calling for cardiovascular outcome trials when developing new drugs for type 2 diabetes mellitus to ensure that there was not substantial cardiovascular risk. The focus was on traditional major adverse cardiac outcomes, including cardiovascular death, myocardial infarction, and stroke. Large trials have enabled investigators to determine the effect of new drugs on a variety of cardiovascular outcomes. It has become clear that certain glucose-lowering treatments have important effects on reducing the development of heart failure and on renal protection.1 There has been less focus on the impact on the development of atrial fibrillation.Atrial fibrillation is common in older populations that have coronary disease and diabetes mellitus. Diabetes mellitus is an independent predictor of the development of atrial fibrillation,2 and diabetes mellitus is part of the CHA2DS2-VASc score as an independent predictor of stroke in patients with atrial fibrillation. Atrial fibrillation is also common in patients with heart failure, and it is associated with adverse outcome in patients with heart failure with and without symptomatic heart failure and with reduced and preserved ejection fraction.3 Preventing atrial fibrillation in populations at risk, including those with diabetes mellitus and risk of heart failure, is an important goal, to prevent symptoms, stroke, and worsening heart failure related to atrial fibrillation. Many treatments for patients with heart failure that reduce the risk of cardiovascular death and heart failure hospitalizations have been shown to reduce the risk of developing atrial fibrillation, including angiotensin-converting enzyme inhibitors,4 angiotensin receptor antagonists,5 mineralocorticoid receptor antagonists,6 β-blockers,7 but not sacubitril valsartan (compared with enalapril).8In the current issue of Circulation, Zelniker and colleagues9 report the risk of atrial fibrillation or flutter in patients with type 2 diabetes mellitus and multiple risk factors or established atherosclerotic cardiovascular disease, according to randomized treatment assignment in DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events). Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced the relative risk of atrial fibrillation by 19% (hazard ratio, 0.81 [95% CI, 0.68–0.95]), 264 versus 325 patients with atrial fibrillation events. The reduction in atrial fibrillation events was consistent regardless of the presence of atrial fibrillation, heart failure, and established atherosclerotic cardiovascular disease at baseline.The coprimary outcomes of DECLARE were cardiovascular death, myocardial infarction, and stroke (that was not significantly reduced), and cardiovascular death and heart failure hospitalization, which was reduced by 17%, mainly because of a 27% relative risk reduction in heart failure hospitalization. In fact, each of the large cardiovascular trials of SGLT2 inhibitors in patients with diabetes mellitus and in patients with heart failure has shown substantial reductions in heart failure events.10 The robust and consistent reductions in hospitalization for heart failure across the development programs were not anticipated during the design and conduct of the first series of cardiovascular outcome trials. Therefore, systematic collection of key baseline information often analyzed in association with heart failure events was not performed or reported including details of the history of atrial fibrillation or important parameters such as left ventricular ejection fraction. In addition, information about incident atrial fibrillation during the trials was typically reported as adverse events, including in the current article from the DECLARE trial. This reporting generally depends on investigators identifying events and reporting them in a relatively unstructured way. Events are only reported when there is active detection, and there is no assessment as to whether events did not occur. Thus, when events are not reported, there is uncertainty as to whether the events did not occur. Without clear prospective definitions, events may be reported that should not have been, and there tends to be underestimation of the true incidence of events in comparison to when collected using a case report form that calls for systematic assessment of whether or not events occurred.11,12Other than the present report, the effects of SGLT2 inhibitors on atrial fibrillation have not been reported in detail from the cardiovascular outcome trials, although some information is available from adverse event reporting, summarized in the Table.13–15 Two of the 3 cardiovascular outcome trials of patients with diabetes mellitus reported lower rates of atrial fibrillation with the SGLT2 inhibitor, but the absolute reduction was small, in the range of 0.1% to 0.2% per year. There was no consistent reduction in stroke with SGLT2 inhibitors in the trials, something one might expect if there was a large reduction in atrial fibrillation.Table. Atrial Fibrillation in Cardiovascular Trials of SGLT2 InhibitorsTrial/ProgramBaseline History of AFNew AF During the TrialHazard Ratio (95% CI) of SGLT2 Inhibitor Versus Placebo on StrokeSGLT2 InhibitorPlaceboEMPA-REG NCT011316765.8%2.3%*1.6%1.18 (0.89–1.56)CANVAS NCT019897546.0%0.56%/y0.61%/y0.87 (0.69–1.09)DECLARE NCT017305346.5%0.78%/y0.96%/y1.01 (0.84−1.21)†DAPA-HF NCT0303612438.3%1.1%‡1.6%Not reportedAF indicates atrial fibrillation; CANVAS, A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus; DAPA-HF, Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure; DECLARE, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; and SGLT2, sodium-glucose cotransporter-2.*Described as "based on the ECG."13†Ischemic stroke.‡From serious adverse event table in the appendix of the results manuscript.15In the current report from DECLARE-TIMI 58, Zelniker and colleagues9 perform a number of sensitivity analyses to address the limitations of using adverse event reporting to detect events of atrial fibrillation. They find consistent results removing events related to hospital admissions for heart failure, because lower rates of atrial fibrillation could reflect the lesser degree of monitoring that occurs in such admissions, which were substantially reduced with SGLT2 inhibitors.Is this reduction in atrial fibrillation with dapagliflozin a real finding? The fact that many beneficial treatments for chronic heart failure have found reductions in atrial fibrillation supports the likelihood that dapagliflozin, which is highly effective at preventing heart failure, could have this effect that may be attributable to the reduction in heart failure and atrial stretch rather than a direct effect on atrial tissue. Moreover, several other effects now recognized for SGLT2 inhibitors include processes that mechanistically may affect atrial fibrillation. These effects include reduction in body weight, blood pressure, improved myocyte energetics, and arterial compliance. However, the facts that atrial fibrillation was a secondary outcome without rigorous prospective collection, that the effects are not seen consistently across trials, and that the absolute effect is small, all call for additional study regarding the reliability and clinical importance of this finding.In summary, this report provides evidence that dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes mellitus and coronary disease or multiple risk factors. It also raises the question of how to determine when effects on a secondary outcome, in particular, one collected without the rigor of systematic collection using prospective definitions and case report forms, are reliable.DisclosuresDr Granger has received research grants from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Armetheon, AstraZeneca, US Food & Drug Administration, GlaxoSmithKline, The Medicines Company, Medtronic Foundation, Medtronic Inc., and Novartis; consulting fees from Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, Abbvie, Armetheon, Astra Zeneca, Eli Lilly, Gilead, GlaxoSmithKline, Hoffmann-La Roche, The Medicines Company, National Institutes of Health, Novartis, Sirtex, Verseon, Apple, Medscape, LLC, Merck, Novo Nordisk, Roche Diagnostics, and Rho Pharmaceuticals. Current Conflicts of Interest listed at https://dcri.org/about-us/conflict-of-interest/. Dr Mahaffey's financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circChristopher B. Granger, MD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27701. Email [email protected]duke.eduReferences1. Sharma A, Pagidipati NJ, Califf RM, McGuire DK, Green JB, Demets D, George JT, Gerstein HC, Hobbs T, Holman RR, et al. Impact of regulatory guidance on evaluating cardiovascular risk of new glucose-lowering therapies to treat type 2 diabetes mellitus: lessons learned and future directions.Circulation. 2020; 141:843–862. doi: 10.1161/CIRCULATIONAHA.119.041022LinkGoogle Scholar2. Seyed Ahmadi S, Svensson AM, Pivodic A, Rosengren A, Lind M. 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Pieske B, Heinzel F and Hohendanner F (2021) Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation, International Journal of Molecular Sciences, 10.3390/ijms22115937, 22:11, (5937) Related articlesEffect of Dapagliflozin on Atrial Fibrillation in Patients With Type 2 Diabetes MellitusThomas A. Zelniker, et al. Circulation. 2020;141:1227-1234 April 14, 2020Vol 141, Issue 15 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.045864PMID: 32282249 Originally publishedApril 13, 2020 Keywordsatrial fibrillationsodium-glucose cotransporter 2 inhibitorsdiabetes mellitus, type 2Editorialsheart failurePDF download Advertisement SubjectsMeta AnalysisThrombosis